Contribution of mitochondrial reactive oxygen species to increased pulmonary vasoconstrictor reactivity following intermittent hypoxia

Abstract

Reactive oxygen species (ROS) have been implicated in mediating intermittent hypoxia (IH)‐induced pulmonary hypertension and associated increases in pulmonary vasoconstrictor reactivity to endothelin‐1 (ET‐1). Based on evidence that acute hypoxia increases mitochondrial ROS generation to elicit pulmonary arterial constriction, we hypothesized that IH enhances pulmonary vasoconstrictor reactivity to ET‐1 via production of mitochondrial ROS. To test this hypothesis, we measured vasoconstrictor responses to ET‐1 in the presence of the mitochondrial ROS scavenger MITO‐CP (0.5 μM) or the complex I inhibitor rotenone (10 μM) in endothelium‐disrupted, pressurized pulmonary arteries (~130 μm inner diameter) from IH (3 min cycles of 5% O2, 5% CO2/air flush, 7 hr/day, 4 wk) and Sham (air/air cycling for equal duration) rats. Effects of IH on basal and ET‐1‐induced O2− generation were also assessed in pressurized, dihydroethidium (DHE)‐loaded arteries by fluorescence microscopy. Both MITO‐CP and rotenone attenuated ET‐1‐mediated vasoconstriction in IH arteries and normalized responses between groups. Furthermore, IH increased both basal and ET‐1‐stimulated DHE fluorescence in isolated pulmonary arteries. We conclude that mitochondrial ROS contribute to augmented pulmonary vasoconstrictor reactivity to ET‐1 following IH.